1. Field of the Invention
The present invention relates to the treatment and prevention of atherosclerosis and other proliferative diseases associated with neovascularization within the cardiovascular system. In particular, the present invention provides methods and systems for using photodynamic therapy to modify the atherosclerotic disease process.
2. Description of the Related Art
Cardiovascular disease (CVD) is a major health problem throughout the world. In the United States alone, roughly 2600 people die each day as a result of cardiovascular disease. CVD includes dysfunctional conditions of the heart, arteries, and veins that supply oxygen to vital life-sustaining areas of the body like the brain, the heart itself, and other vital organs. Two prominent forms of cardiovascular disease are cardiovascular obstructive disease and acute coronary syndrome.
Cardiovascular obstructive disease, also referred to as ischemic heart disease or stenosis, results from obstruction of blood flow to the heart. In general, this results because excess fat or plaque deposits are narrowing the blood vessels that supply oxygenated blood to the heart. Excess buildup of fat or plaque are respectively termed arteriosclerosis and atherosclerosis. These blockages usually result in oxygen-starvation of heart muscle tissue and subsequent injury to the tissue, which is, in most cases, irreversible and may prove fatal. Equally significant is inadequate oxygen flow to the brain, which may cause a stroke.
In recent years, a great deal of research has been devoted to the treatment of vascular obstructive disease, and treatment methods such as balloon angioplasty have become standard treatment for stenosis. In this procedure, once the location of stenosis has been identified by any of a variety of known techniques, an angioplasty catheter is inserted into the blocked vessel using a guidewire. A balloon on the catheter is inflated at the blockage site to push open the blocked vessel.
Unfortunately, however, in many cases, vessels recoil to original narrowed lumen or re-stenose (became re-blocked with plaque and/or scar tissue resulting from injury caused by distension of the vessel by the balloon) within a short period of time. Attempts to prevent recoil and/or restenosis include the use of stent devices that are permanently implanted within the vessel to hold it open at the site of the angioplasty and thereby prevent elastic recoil of the vessel following angioplasty. While this is successful in preventing recoil, it was found that the stent itself provided a stimulus for restenosis. As a result, new stents were created that have coatings to reduce the body's response to the stent including those on which a drug (typically an anti-proliferative agent) was incorporated into the coating to further reduce the incidence of restenosis. These drug-eluting stents are now widely used for treatment of patients with angina, the symptomatic consequence of coronary arteries that have become significantly narrowed by atherosclerotic plaque.
Photodynamic therapy (PDT) has been explored as an alternative approach to treating cardiovascular obstructive disease and restenosis. Attempts have been made to use light treatment, e.g., PDT, as the initial treatment for blood-flow limiting vascular occlusions in patients with atherosclerotic disease. For example, U.S. Patent Publication No. 2002/0183301 describes a method in which a photosensitizer is delivered locally or systemically to a patient, and light is applied in the wavelength range 390 to 610 nm to excite the photosensitizer. The chosen wavelength is said to reduce light penetration to underlying blood vessel tissue and, thereby, reduce injury to that tissue. The PDT is said to inhibit, stabilize, or reduce occlusions in the cardiovascular system. However, because of the wavelength of light used, blood has to be removed from the region between the light and the targeted tissue, because hemoglobin in the blood might otherwise absorb the light. This publication also cautions that treatment should avoid damage to the myocardial tissue underlying the vessel, or lung tissue, and that blood intervening between the light and these tissues acts as a protective shield by absorbing the light.
U.S. Patent Publication No. 2004/0208855 describes the treatment of intimal hyperplasia or stenosis in arteriovenous fistula with PDT. In particular, this publication deals with the prevention or treatment of these conditions in grafts or fistulas created for the purpose of conducting hemodialysis. These grafts or fistulas become obstructed over time by proliferation and thrombosis. In one embodiment, a vein exterior (adventitia layer) is exposed to 690 nm wavelength light for 40 minutes; this so-called “low dose” PDT is said to be preferred to prevent massive destruction of vessel tissue. The dose provided is said to be a function of photosensitizer concentration, intensity of light irradiation, and exposure time.
The use of PDT to treat restenosis has been described, e.g., in U.S. Pat. Nos. 5,370,608 and 5,417,653. However, light treatment is not widely used, if at all, to prevent or reduce restenosis after angioplasty, with or without stenting.
Acute coronary syndrome is a subset of serious sudden-onset cardiovascular diseases, including unstable angina, acute myocardial infarction, and sudden cardiac death. Often, acute coronary syndrome occurs in patients who have no documented history of cardiovascular disease. The cardiovascular diseases associated with acute coronary syndrome are frequently caused by erosion or rupture of a specific kind of active atheromatous plaque known as a “vulnerable plaque.” This plaque is also referred to referred to as a “thin-capped fibroatheroma”. See, e.g., Mamoo Nakamura, et al., Reviews in Cardiovascular Medicine, 2004, vol. 5 Suppl. 2 (s22-33).
A cross-section of a vein partially occluded by a vulnerable plaque is shown in FIG. 1. As depicted, the blood vessel has an open area through which blood can flow (the lumen) and is partially obstructed by a structure that has a fibrous cap and a lipid core. The lipid-rich core has been suggested to be the most powerful plaque type because it contains macrophages that produce tissue factors as well as thrombogenic lipid forms, such as lipoprotein (a). Accordingly, when this lipid core is exposed to blood (e.g., when the plaque fibrous cap erodes or ruptures), there is high risk of forming thrombus that can occlude the vessel with potential serious consequences for the subject.
In contrast to the vast majority of plaque lesions, which remain relatively stable and slowly occlude the vasculature, vulnerable plaques have higher frequency of rupture and are the leading causative agent of heart attacks, strokes, and cases of sudden death, recently estimated to be as high as 80-85%. Vulnerable plaques are structurally and functionally distinguishable from stable atherosclerotic plaques, but are almost impossible to easily detect or distinguish from quiescent or stable atherosclerotic plaques using current imaging modalities, which do not give sensitive information on plaque components and cap thicknesses (e.g., MRI, CT, myocardial perfusion imaging, angiography, intravascular ultrasound, thermography, OCT, reflectance, and spectroscopy).
Post-mortem evidence suggests that vulnerable plaque rupture occurs most frequently in areas of the coronary arteries that are less than 50% stenosed. Current therapies to ameliorate the occlusive effects of atherosclerotic plaques, such as bypass surgery and angioplasty, which focus on areas with greater than 50% stenosis, rarely remove vulnerable plaques or reduce the incidence of acute coronary syndrome. Drugs currently being developed to treat such plaques include, e.g., statins and ACE inhibitors.
However, given the significant health problems associated with acute coronary syndromes, and in light of the recent advancements in detecting the presence of underlying vulnerable plaques, there is clearly an immediate need for improved methods and devices for treating acute coronary syndromes, including, e.g., methods and devices to prevent the growth and rupture of vulnerable plaques through PDT.